title: Interferon γ-induced intratumoral expression of CXCL9 alters the local distribution of T cells following immunotherapy withListeria monocytogenes.
abstract: The ability ofListeria monocytogenes-based anticancer vaccines to induce tumor regression depends on the responsiveness of malignant cells to interferon γ (IFNγ). Inhibition of IFNγ limits the recruitment of T cells to the tumors of vaccinated mice. We hypothesized that vaccination with immunotherapeuticL. monocytogenesinduces the IFNγ-dependent production of chemokines that regulate the migration of tumor-infiltrating T cells. To gain further insights into this issue, we examined the chemokine responses of a transplantable, human papillomavirus (HPV)-immortalized murine tumor model (TC-1) following the administration of aL. monocytogenes-based immunotherapeutic agent that expresses E7 from HPV-16. Here, we report that the administration ofL. monocytogenes-based anticancer vaccines increases the secretion of chemokine (C-X-C motif) ligand 9 (CXCL9), and CXCL10 by tumors, hence favoring the recruitment of T cells bearing the cognate chemokine (C-X-C motif) receptor 3 (CXCR3). Furthermore, the expression of CXCL9, but not CXCL10, in TC-1 tumors was significantly reduced upon anti-IFNγ antibody treatment. CXCL9 was highly expressed by TC-1 cells following the administration of IFNγ and tumor necrosis factor α (TNFα), in vitro. Moreover, the inhibition of CXCL9 in TC-1 cells reduced the proportion of CD8+T cells infiltrating tumors in vaccinated mice, while increasing that of CD4+T cells, thus altering T-cell subset distribution. We conclude that the administration ofL. monocytogenes-based anticancer vaccines regulates TH1 chemokine responses and that malignant cells are an important source of these chemokines.
authors.affiliation: Department of Microbiology; Perelman School of Medicine; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Guirnalda
authors.forename: Laurence
authors.initials: L
authors.lastname: Wood
authors.forename: Radhika
authors.initials: R
authors.lastname: Goenka
authors.forename: Joel
authors.initials: J
authors.lastname: Crespo
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Paterson
keywords: IFNγ receptor; Listeria monocytogenes; T cells; chemokine; immunotherapy; tumor